title: Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: possible implications for GAI pathogenesis.
abstract: Glutaric (GA) and 3-hydroxyglutaric (OHGA) acids accumulate in glutaric acidemia I (GAI), a neurometabolic disease characterized by acute striatal degeneration and chronic progressive cortical atrophy. To explore the hypothesis that astrocytes are involved in GAI pathogenesis and targets of accumulating metabolites, we determined the effects of GA and OHGA on cultured rat cortical astrocytes. Remarkably, both acids induced mitochondria depolarization and stimulated proliferation in confluent cultures without apparent cell toxicity. Newborn rats injected with GA systemically also showed increased cell proliferation in different brain regions. Most of the proliferating cells displayed markers of immature astrocytes. Antioxidant iron porphyrins prevented both mitochondria dysfunction and increased in vitro and in vivo proliferation, suggesting a role of oxidative stress in inducing astrocytosis. Taken together, the data suggest that mitochondrial dysfunction induced by GA metabolites causes astrocytes to adopt a proliferative phenotype, which may underlie neuronal loss, white matter abnormalities and macrocephalia characteristics of GAI.
authors.affiliation: Cellular and Molecular Neurobiology Department, Instituto Clemente Estable (IIBCE), Montevideo, Uruguay.
authors.forename: Silvia
authors.initials: S
authors.lastname: Olivera
authors.forename: Anabel
authors.initials: A
authors.lastname: Fernandez
authors.forename: Alexandra
authors.initials: A
authors.lastname: Latini
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Rosillo
authors.forename: Gabriela
authors.initials: G
authors.lastname: Casanova
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.forename: Patricia
authors.initials: P
authors.lastname: Cassina
authors.forename: Luis
authors.initials: L
authors.lastname: Barbeito
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D001921:Brain / Q000254:growth & development / Q000502:physiology; D020739:Brain Diseases, Metabolic, Inborn / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology; D002452:Cell Count; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005977:Glutarates / Q000378:metabolism* / Q000494:pharmacology; D007150:Immunohistochemistry; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D011166:Porphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C108959:3-hydroxyglutaric acid; D000873:Anthracenes; D000975:Antioxidants; D002070:Butadienes; D005977:Glutarates; D009570:Nitriles; D011166:Porphyrins; C113580:U 0126; C432165:pyrazolanthrone; C035736:glutaric acid